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Drug Design, Development and Therapy 2014:8 129–163

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http://dx.doi.org/10.2147/DDDT.S53522

novel n-substituted aminobenzamide scaffold derivatives targeting the dipeptidyl peptidase-iV enzyme

Qosay a al-Balas1

Munia F sowaileh1

Mohammad a hassan1

amjad M Qandil1,2

Karem h alzoubi3

nizar M Mhaidat3

ammar M almaaytah4

Omar F Khabour5

1Department of Medicinal chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of science and Technology, irbid, Jordan; 2Pharmaceutical sciences Department, college of Pharmacy, King saud bin abdulaziz University for health sciences, riyadh, saudi arabia; 3Department of clinical Pharmacy, Faculty of Pharmacy, Jordan University of science and Technology, irbid, Jordan; 4Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of science and Technology, irbid, Jordan; 5Department of Medical laboratory sciences, Faculty of applied Medical sciences, Jordan University of science and Technology, irbid, Jordan

correspondence: Qosay a al-Balas; Munia F sowaileh Department of Medicinal chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of science and Technology, PO Box 3030, irbid 22110, Jordan Tel +962 776 337 216 Fax +962 272 01 075 email [email protected]; [email protected]

Background: The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion

of meals enhance insulin release to the blood, and DPP-IV inactivates these incretins within a

short period and stops their action. Inhibition of this enzyme escalates the action of incretins

and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition

of this enzyme will lead to better control of blood sugar levels.

Methods: In this study, computer-aided drug design was used to help establish a novel N-substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software

available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and

assess their mode of binding to the active site of the DPP-IV enzyme. The designed compounds

were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The

synthesized compounds were characterized using proton and carbon nuclear magnetic resonance,

mass spectrometry, infrared spectroscopy, and determination of melting point.

Results: Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against

DPP-IV than the reference compounds, with the most active compounds scoring 38% activity

at 100 µM concentration.Conclusion: The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds

possessing the same scaffold.

Keywords: diabetes mellitus, dipeptidyl peptidase-IV, aminobenzamide derivatives, hypoglycemic activity, CDOCKER software

IntroductionDiabetes is a group of metabolic disorders characterized by hyperglycemia caused by

insulin deficiency (type 1 diabetes) or insulin resistance (type 2 diabetes).1 The classical

symptoms of diabetes are polyuria, polydipsia, and polyphagia, with other symptoms

including weight loss, fatigue, frequent infections, blurred vision, slower healing of

injuries, and numbness in the extremities.2 The impact of diabetes on patients’ lives and

on society’s economy elicits a compelling need to deal with diabetes more seriously.3

The main focus of treatment for diabetes is to maintain blood glucose levels in the

normal range throughout the day. Tight control of glucose levels is essential in slowing

progression of the disease and in preventing its complications.4

A valid target when designing antidiabetic agents is inhibition of the dipeptidyl

peptidase-IV enzyme (DPP-IV). DPP-IV was discovered in 1966, but its role in glucose

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al-Balas et al

homeostasis took some time to become clear,5 and it was

not until 1998 that inhibition of DPP-IV was suggested as a

possible route to manage diabetes.6 Since then, a number of

DPP-IV inhibitors have appeared in the literature. DPP-IV

is an example of great demand making a novel target a per-

fect investment for pharmaceutical companies, and this has

resulted in four drugs being approved by the US Food and

Drug Administration and six drugs being marketed world-

wide in less than 15 years.7

DPP-IV is composed of a single polypeptide chain con-

taining 766 amino acids. It can be roughly divided into three

regions, ie, a catalytic region, a cysteine-rich region, and a

highly glycosylated region, in addition to a transmembrane

domain at the N-terminus in the case of membrane-bound

DPP-IV. DPP-IV monomers join to form homodimers.8,9

DPP-IV is a serine-type peptidase, meaning that its cata-

lytic activity is essentially based on an interaction with the

amino acid serine at its active site.10 The catalytic domain of

DPP-IV consists of Ser630, Asp708, and His740.11 Although

distant from the Ser-Asp-His catalytic triad, Glu205 and

Glu206 play a critical role in the activity of this enzyme.12

An important feature of the active site of DPP-IV is

the presence of a tight hydrophobic pocket, known as the

S1 pocket (see Figure 1). This pocket is responsible for the

specificity of the DPP-IV substrate for proline and its toler-

ance for alanine and glycine.13

The rationale for this work is based on a previous inves-

tigation performed in our laboratory where screening using a

DPP-IV enzyme assay kit indicated that compound 1 shown in

Figure 2 has a 28% inhibitory effect on DPP-IV; this structure

has subsequently served as a guide compound for the design

of a series of DPP-IV inhibitors. The present work describes

the synthesis of 69 novel N-substituted aminobenzamide

derivatives that were fully characterized with 1H nuclear

magnetic resonance (NMR), 13C NMR, and mass and infrared

spectroscopy, along with evaluation of their DPP-IV inhibition

activity. Using computer modeling techniques to introduce

modifications that we assumed would improve binding,

a series of aminobenzamides was investigated.

Materials and methodsin silico dockingA search for the DPP-IV enzyme crystal structure in the

Protein Data Bank14 was conducted on November 30, 2011

using the search terms “DPP-IV” and “dipeptidyl peptidase-

IV”. The hits were limited to enzymes extracted from Homo

sapiens only, and each hit was inspected to check the protein,

ligand, and resolution. In the “Prepare Protein” protocol,

the default parameter values were mostly kept the same.

The proposed compounds were prepared using the “Prepare

Ligand” protocol, also with default parameters.

Docking was accomplished using the CDOCKER pro-

tocol available from Accelrys (San Diego, CA, USA).15 The

following parameters were used: Top Hits, 10; Random

Conformations, 10; Orientations to Refine, 10; Forcefield,

CHARMM; and Use Full Potential, False. Careful inspec-

tion of all crystal structures showed that the following amino

acids were involved in binding the substrates (amino acids

are arranged according to the frequency of bond formation in

descending order): H-bond-forming amino acids, ie, Glu206,

Tyr662, Glu205, Arg125, Asn710, Tyr547, Arg358, Tyr631,

Ser209, Tyr585, Val207, and Tyr666; and Pi-Pi interaction-

forming amino acids, ie, His740, Tyr662, Phe337, Tyr457,

Arg125, Arg358, and Trp659.

chemistryBulk solvents and chemicals were purchased through local

vendors without any further purification or distillation. The

progress of reactions was qualitatively analyzed by thin

layer chromatography performed on Merck aluminum thin

layer chromatography plates (DC Kieselgel 60 F254). An

ultraviolet lamp was used to visualize the thin layer chro-

matography plate. New compounds were characterized by 1H-NMR and 13C-NMR using a 400 mHz Avance Ultrashield

spectrometer (Bruker, Ettlingen, Germany); the spectra were

obtained in parts per million using automatic calibration to

the residual proton peak of the solvent, ie, dimethylsulfoxide

(DMSO)-d6. The infrared spectra of the synthesized com-

pounds were recorded on a Thermo-Nicolet Avatar 360 FT-IR,

(Thermo Fisher Scientific, Rockville, MD, USA). A liquid

chromatography-tandem mass spectrometry system (API

3200, Applied Biosystems-MDS SCIEX, Foster City, CA,

USA), employing positive mode, was used to characterize the

compounds, with the electrospray ionization source operated

at 5.0–5.5kV, the capillary heater at 350°C, and a sheath gas pressure of 45 psi. The enzyme activity plates were read using

a universal microplate reader (ELx800, Bio-Tek Instruments

Inc, Winooski, VT, USA).

synthesis of anilinoketones from substituted α-bromoketones (52–84, 87, 88)Amino-N-substituted phenylbenzamide (one equivalent),

potassium carbonate (one equivalent), and α-bromoketone (one equivalent) were dissolved in dimethylformamide (20 mL). The

reaction mixture was stirred for 8 hours. The reaction contents

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Drug Design, Development and Therapy 2014:8

VAL656

TYR631

S1 pocket

.Y632TYR547

TRP629

A

B

HIS740

SE 0

SER209

26

SERA:209

Residue interaction

Electrostatic

van der Waals

Covalent bond

Water

VALA:656 VAL

A:711

SERA:630

TYRA:631TYR

A:547

TYRA:662

TYRA:666

TRPA:659

ASNA:710

GLUA:205

OON

N

N

GLUA:206

ARGA:125

PHEA:357

SERA:630

HISA:740

Metal

Figure 1 (A) Three-dimensional X-ray structure of the binding pocket of DPP-iV with an inhibitor (vildagliptin). (B) Two-dimensional diagram of vildagliptin binding DPP-iV active site showing different types of interactions. Abbreviation: DPP-iV, dipeptidyl peptidase-V.


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n-substituted aminobenzamide scaffold derivatives targeting DPP-iV

were then poured over water with stirring, and the mixture was

left until the product precipitated. The product was then filtered,

dried, and recrystallized from ethanol.

4-(2-oxo-2-phenylethylamino)- n-phenylbenzamide (52)Prepared by reacting 23 (1.06 g, 5 mmol) and H1 (1 g, 5 mmol)

in the presence of potassium carbonate (0.5 g, 5 mmol), to

yield 0.6 g (36%) of 52 as light yellow crystals. Melting

point 186°C–188°C; IR 3,375, 3,294, 3,039, 1,685, 1,641, 1,319 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.79 (d, 2H, CH2, J = 5.4 Hz), 6.53 (t, 1H, NH-Ar, J =5.3 Hz), 6.75 (d,

2H, Ar-H, J = 8.5 Hz), 7.04 (t, 1H, Ar-H, J =7.2 Hz), 7.31 (t,

2H, Ar-H, J =7.8 Hz), 7.58 (t, 2H, Ar-H, J =7.6 Hz), 7.68 (d,

1H, Ar-H, J = 7.3 Hz), 7.74 (d, 2H, Ar-H, J = 8.2 Hz), 7.77

(d, 2H, Ar-H, J = 8.4 Hz), 8.09 (d, 2H, Ar-H, J = 8 Hz) 10.23

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(s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 52.13, 114.12, 122.85, 124.37, 125.65, 130.56, 131.12, 131.47, 131.83,

136.30, 137.64, 142.32, 153.79, 167.98, 198.85; MS (EI)

m/z: 331 (M+, 100%).

3-(2-oxo-2-phenylethylamino)- n-phenylbenzamide (53)Prepared by reacting 24 (3 g, 14.1 mmol) and H1 (2.81 g,

14.1 mmol) in the presence of potassium carbonate (1.41 g,

14.1 mmol), to yield 2.7 g (58%) of 53 as yellow crystals.

Melting point 204°C–205°C; IR 3,381, 3,346, 3,062, 1,685, 1,654, 1,363 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.77 (d, 2H, CH

2, J=5.3 Hz), 6.14 (t, 1H, NH-Ar, J=5.3 Hz),

6.91 (d, 1H, Ar-H, J=7.7 Hz), 7.09 (t, 1H, Ar-H, J=7.6 Hz), 7.16 (d, 1H, Ar-H, J=7.4 Hz), 7.24 (m, 2H, Ar-H), 7.34 (t, 2H, Ar-H, J=7.8 Hz), 7.57 (t, 2H, Ar-H, J=7.5 Hz), 7.68 (t, 1H, Ar-H, J=7.3 Hz), 7.77 (d, 2H, Ar-H, J=8 Hz), 8.09 (d, 2H, Ar-H, J=7.6 Hz), 10.10 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 52.44, 114.02, 117.97, 118.26, 123.00, 126.18, 130.53, 131.21, 131.48, 136.27, 137.71, 138.53, 141.89,

150.87, 168.95, 199.19; MS (EI) m/z: 331 (M+, 100%).

4-(2-oxo-2-phenylethylamino)- n-p-tolylbenzamide (54)Prepared by reacting 25 (3.41 g, 15.1 mmol) and H1 (3 g,


15.1 mmol), to yield 1.35 g (26%) of 54 as light yellow crys-

tals. Melting point 198°C–199°C; IR 3,400, 3,057, 1,678, 1,658, 1,315 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 2.25 (s, 3H, CH

3), 4.78 (s, 2H, CH

2), 6.6 (s, 1H, NH-Ar), 6.74

(d, 2H, Ar-H, J=8.2 Hz), 7.1 (d, 2H, Ar-H, J=7.4 Hz), 7.59 (m, 4H, Ar-H), 7.65 (m, 1H, Ar-H), 7.75 (d, 2H, Ar-H, J=8 Hz), 8.08 (d, 2H, Ar-H, J=7.4 Hz), 9.72 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 20.95, 49.97, 111.94, 120.75, 122.29, 128.41, 129.34, 129.37, 129.58, 132.40, 134.17, 135.49, 137.58,

151.54, 165.64, 196.75; MS (EI) m/z: 345 (M+, 100%).

3-(2-oxo-2-phenylethylamino)- n-p-tolylbenzamide (55)Prepared by reacting 26 (4.6 g, 20.3 mmol) and H1 (4.05 g,


20.3 mmol), to yield 4.8 g (69%) of 55 as off-white crystals.

Melting point 210°C–211°C; IR 3,381, 3,062, 1,681, 1,651, 1,330 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 2.27 (s, 3H, CH3), 4.79 (d, 2H, CH2, J = 3.2 Hz), 6.16 (s, 1H, NH-Ar), 6.91

(d, 1H, Ar-H, J = 7.8 Hz), 7.16 (d, 2H, Ar-H, J = 7.2 Hz), 7.22

(m, 3H, Ar-H), 7.59 (t, 2H, Ar-H, J =7.1 Hz), 7.66 (d, 2H, Ar-H,

J = 9.6 Hz), 7.69 (t, 1H, Ar-H, J =7.8 Hz), 8.11 (d, 2H, Ar-H,

J = 7.3 Hz), 10.02 (s,1H, CO-NH).; 13C-NMR (DMSO-d6):

δ 19.65, 48.98, 110.53, 114.42, 114.66, 119.49, 127.06, 127.90, 127.98, 128.10, 131.54, 132.76, 134.25, 135.15, 135.94,

147.38, 165.21, 195.67; MS (EI) m/z: 345 (M+, 100%).

4-(2-oxo-2-phenylethylamino)- n-m-tolylbenzamide (56)Prepared by reacting 27 (3.41 g, 15.1 mmol) and H1 (3 g,


15.1 mmol), to yield 1.1 g (21%) of 56 as white crystals. Melting

point 161°C–162°C; IR 3,381, 3,292, 1,681, 1,658, 1,303 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 2.29 (s, 3H, CH3), 4.79 (d, 2H, CH2, J = 5.1 Hz), 6.53 (t, 1H, NH-Ar, J =5 Hz), 6.76

(d, 2H, Ar-H, J = 8.3 Hz), 6.86 (d, 1H, Ar-H, J = 7.2 Hz), 7.18

(t, 1H, Ar-H, J =7.7 Hz), 7.56 (m, 2H, Ar-H), 7.69 (t, 1H, Ar-H,

J =7.2 Hz), 7.79 (d, 2H, Ar-H, J = 8.3 Hz), 8.09 (d, 2H, Ar-H,

J = 7.8 Hz), 9.75 (s, 1H, CO-NH).; 13C-NMR (DMSO-d6):

δ 21.87, 50.17, 112.17, 118.12, 121.54, 122.54, 124.42, 128.57, 128.98, 129.50, 129.83, 134.31, 135.70, 138.27, 140.23,

151.78, 165.98, 196.90; MS (EI) m/z: 345 (M+, 100%).

3-(2-oxo-2-phenylethylamino)- n-m-tolylbenzamide (57)Prepared by reacting 28 (226.27 g, 8.4 mmol) and H1 (1.67 g,


8.4 mmol), to yield 1.4 g (46%) of 57 as light yellow crystals.

Melting point 177°C–178°C; IR 3,365, 3,282, 3,059, 1,691, 1,643, 1,332 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 2.46 (s, 3H, CH

3), 4.95 (s, 2H, CH

2), 3.57 (d, 1H, NH-Ar, J=4.6 Hz),

7.07 (s, 2H, Ar-H), 7.34 (d, 1H, Ar-H, J=3.9 Hz), 7.39 (m, 3H, Ar-H), 7.74 (m, 3H, Ar-H), 7.79 (s, 1H, Ar-H), 7.84 (t, 1H,

Ar-H, J=5.8 Hz), 8.26 (d, 2H, Ar-H, J=4.4 Hz), 10.19 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 21.22, 49.85, 111.41, 115.39, 115.63, 117.61, 121.04, 124.26, 127.90, 128.41,

128.46, 128.85, 133.62, 135.13, 135.96, 137.73, 139.19,

148.24, 166.24, 196.57; MS (EI) m/z: 345 (M+, 100%).

n-(4-chlorophenyl)-4-(2-oxo-2- phenylethylamino)benzamide (58)Prepared by reacting 29 (4 g, 16.1 mmol) and H1 (3.2 g,

16.1 mmol) in the presence of potassium carbonate

O

OHN

NH

O

Figure 2 structure of compound 1, as the starting scaffold.

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(1.6 g, 16.1 mmol), to yield 3 g (55%) of 58 as light yellow

crystals. Melting point 220°C–222°C; IR 3,392, 3,360, 3,041, 1,672, 1,651, 1,338, 1,089 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 4.79 (d, 2H, CH2), 6.56 (s, 1H, NH-Ar), 6.76 (s, 2H, Ar-H), 7.34 (s, 2H, Ar-H), 7.55 (s, 2H, Ar-H), 7.67

(s, 1H, Ar-H), 7.78 (s, 4H, Ar-H), 8.07 (s, 2H, Ar-H), 9.95

(s,1H, CO-NH).; 13C-NMR (DMSO-d6): δ 52.10, 114.13, 124.01, 124.28, 129.18, 130.55, 130.99, 131.46, 131.89,

136.29, 137.62, 141.32, 153.92, 168.04, 198.79; MS (EI)

m/z: 365 (M+, 100%).

n-(4-chlorophenyl)-3-(2-oxo-2- phenylethylamino)benzamide (59)Prepared by reacting 30 (2 g, 8 mmol) and H1 (1.6 g, 8 mmol)

in the presence of potassium carbonate (0.8 g, 8 mmol), to

yield 2.12 g (89%) of 59 as yellow crystals. Melting point

230°C–233°C; IR 3,398, 3,344, 3,061, 1,678, 1,647, 1,330, 1,093 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.79 (d, 2H, CH2), 6.56 (s, 1H, NH-Ar), 6.76 (s, 2H, Ar-H), 7.34 (s, 2H,

Ar-H), 7.55 (s, 2H, Ar-H), 7.67 (s, 1H, Ar-H), 7.78 (s, 4H,

Ar-H), 8.07 (s, 2H, Ar-H), 9.95 (s,1H, CO-NH).; 13C-NMR

(DMSO-d6): δ 49.77, 111.39, 115.25, 115.69, 121.75, 127.03, 127.88, 128.45, 128.81, 133.59, 135.07, 135.62, 138.29,

148.25, 166.38, 196.49; MS (EI) m/z: 365 (M+, 100%).

n-(3-chlorophenyl)-4-(2-oxo-2- phenylethylamino)benzamide (60)Prepared by reacting 31 (3.4 g, 13.8 mmol) and H1 (2.74 g,


13.8 mmol), to yield 1.2 g (24%) of 60 as white crystals.

Melting point 183°C–185°C; IR 3,381, 3,302, 3,047, 1,681, 1,658, 1,313, 1,097 cm-1; 1H NMR (400 mHz, DMSO-d6):

δ 4.77 (s, 2H, CH2), 6.15 (s, 1H, NH-Ar), 6.91 (s, 1H, Ar-H), 7.2 (m, 3H, Ar-H), 7.39 (d, 2H, Ar-H, J = 6.7 Hz), 7.57 (s, 2H,

Ar-H), 7.69 (s, 1H, Ar-H), 7.8 (d, 2H, Ar-H, J = 6.6 Hz), 8.09

(d, 2H, Ar-H, J = 4.6 Hz), 10.21 (s, 1H, CO-NH).; 13C-NMR

(DMSO-d6): δ 88.21, 111.78, 117.53, 118.59, 121.73, 127.61, 128.22, 128.36, 128.47, 128.61, 129.30, 132.1, 132.47, 132.8,

140.09, 164.87, 194.89; MS (EI) m/z: 365 (M+, 100%).

n-(3-chlorophenyl)-3-(2-oxo-2- phenylethylamino)benzamide (61)Prepared by reacting 32 (3.7 g, 15.1 mmol) and H1

(3 g, 15.1 mmol) in the presence of potassium carbonate

(1.5 g, 15.1 mmol), to yield 2 g (36%) of 61 as bright yellow

crystals. Melting point 192°C–193°C; IR 3,363, 3,277, 3,066, 1,691, 1,643, 1,311 cm-1; 1H NMR (400 mHz, DMSO-d6):

δ 4.76 (d, 2H, CH2, J=5.4 Hz), 6.16 (t, 1H, NH-Ar, J=5.3 Hz),

6.93 (d, 1H, Ar-H, J=7.9 Hz), 7.14 (d, 2H, Ar-H, J=7.7 Hz), 7.18 (s, 1H, Ar-H), 7.23 (t, 2H, Ar-H, J=7.8 Hz), 7.36 (t, 1H, Ar-H, J=8.1 Hz), 7.57 (t, 2H, Ar-H, J=7.5 Hz), 7.68 (t, 2H, Ar-H, J=7.2 Hz), 7.95 (s, 1H, Ar-H), 8.08 (d, 2H, Ar-H, J=7.2 Hz), 10.25 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 48.95, 110.58, 114.43, 114.97, 117.69, 118.75, 122.29, 127.05, 127.98, 129.42, 132.06, 132.75, 134.67, 139.97,

147.45, 165.69, 195.64; MS (EI) m/z: 365 (M+, 100%).

n-(4-methoxyphenyl)-4-(2-oxo-2- phenylethylamino)benzamide (62)Prepared by reacting 33 (3.6 g, 15.1 mmol) and H1 (3 g,


15.1 mmol), to yield 2.1 g (39%) of 62 as off-white

crystals. Melting point 203°C–205°C; IR 3,367, 3,315, 3,045, 1,685, 1,639, 1,313, 1,253, 1,033 cm-1; 1H NMR

(400 mHz, DMSO-d6): δ 3.14 (s, 3H, CH3), 4.78 (s, 2H,

CH2), 6.50 (s, 1H, NH-Ar), 6.75 (d, 2H, Ar-H, J=6.8 Hz),

6.88 (d, 2H, Ar-H, J=7.3 Hz), 7.56 (m, 2H, Ar-H), 7.63 (d, 2H, Ar-H, J=7.6 Hz), 7.68 (s, 1H, Ar-H), 7.77 (d, 2H, Ar-H, J=6.8 Hz), 8.08 (d, 2H, Ar-H, J=5.9 Hz), 9.72 (s, 1h, CO-NH); 13C-NMR (DMSO-d6): δ 50.17, 55.82, 112.16, 114.32, 122.62, 128.57, 129.51, 129.71, 133.35, 134.33,

135.68, 151.66, 155.87, 165.73, 196.94; MS (EI) m/z: 361

(M+, 100%).

n-(4-methoxyphenyl)-3-(2-oxo-2- phenylethylamino)benzamide (63)Prepared by reacting 34 (1 g, 4.1 mmol) and H1 (0.82 g,


4.1 mmol), to yield 0.9 g (61%) of 63 as bright yellow crys-

tals. Melting point 191°C–193°C; IR 3,365, 3,269, 3,039, 1,708, 1,647, 1,359, 1,082 cm-1; 1H NMR (400 mHz, DMSO-

d6): δ 3.74 (s, 3H, Ar-H), 4.77 (d, 2H, CH2, J=4.9 Hz), 6.12

(t, 1H, NH-Ar, J=4.6 Hz), 6.9 (t, 3H, Ar-H, J=8.7 Hz), 7.13 (d, 1H, Ar-H, J=7.3 Hz), 7.18 (S, 1H, Ar-H), 7.22 (d, 1H, Ar-H, J=7.5 Hz), 7.58 (t, 2H, Ar-H, J=7.3 Hz), 7.65 (d, 2H, Ar-H, J=8.8 Hz), 7.7 (d, 2H, Ar-H, J=7.4 Hz), 8.09 (d, 2H, Ar-H, J=7.6 Hz), 9.95 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 50.32, 55.68, 111.82, 114.19, 115.74, 115.92, 122.47, 128.39, 129.25, 129.33, 133.22, 134.10, 135.59,

136.47, 148.81, 156.11, 166.38, 197.06; MS (EI) m/z: 361

(M+, 100%).

n-(3-methoxyphenyl)-4-(2-oxo-2- phenylethylamino)benzamide (64)Prepared by reacting 35 (3.65 g, 15.1 mmol) and H1


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(1.51 g, 15.1 mmol), to yield 1.9 g (35%) of 64 as light

yellow crystals. Melting point 173°C–175°C; IR 3,377, 3,294, 3,059, 1,687, 1,643, 1,309, 1,280, 1,037 cm-1; 1H

NMR (400 mHz, DMSO-d6): δ 3.74 (s, 3H, CH3), 4.8

(d, 2H, CH2, J=5.3 Hz), 6.56 (t, 2H, NH-Ar, J=5.2 Hz),

6.63 (d, 1H, Ar-H, J=7.9 Hz), 6.77 (d, 2H, Ar-H, J=8.4 Hz), 7.21 (t, 1H, Ar-H, J=8.1 Hz), 7.35 (d, 1H, Ar-H, J=8.1 Hz), 7.47 (s, 1H, Ar-H), 7.58 (t, 2H, Ar-H, J=7.5 Hz), 7.7 (t, 1H, Ar-H, J=7.3 Hz), 7.79 (d, 2H, Ar-H, J=8.4 Hz), 8.09 (d, 2H, Ar-H, J=7.6 Hz), 9.81 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 52.1, 57.57, 108.48, 111.16, 114.12, 115.05, 124.34, 130.55, 131.47, 131.84, 136.31, 137.62,

143.53, 153.82, 162.03, 168.03, 198.84; MS (EI) m/z:

361 (M+, 100%).

n-(3-methoxyphenyl)-3-(2-oxo-2- phenylethylamino)benzamide (65)Prepared by reacting 36 (3.65 g, 15.1 mmol) and H1 (3 g,


15.1 mmol), to yield 1.62 g (30%) of 65 as beige crystals.

Melting point 174°C–176°C; IR 3,365, 3,305, 3,057, 1,693, 1,647, 1,319, 1,265, 1,035 cm-1; 1H-NMR (400 mHz, DMSO-

d6): δ 3.74 (s, 3H, CH3), 4.76 (d, 2H, CH

2, J=2.8 Hz), 6.13 (s,

1H, NH-Ar), 6.66 (d, 1H, Ar-H, J=7.5 Hz), 6.9 (d, 1H, Ar-H, J=7.2 Hz), 7.9 (d, 1H, Ar-H, J=7.2 Hz), 7.18 (s, 1H, Ar-H), 7.22 (t, 2H, Ar-H, J=7.5 Hz), 7.34 (d, 1H, Ar-H, J=7.3 Hz), 7.47 (s, 1H, Ar-H), 7.57 (t, 2H, Ar-H, J=6.3 Hz), 7.66 (t, 1H, Ar-H, J=6.3 Hz), 8.09 (d, 2H, Ar-H, J=7.1 Hz), 10.03 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 45.03, 50.20, 101.21, 104.17, 106.62, 107.73, 110.47, 110.81, 123.10, 123.96,

124.02, 124.50, 128.79, 130.33, 131.12, 135.71, 143.44,

154.62, 161.49, 191.72; MS (EI) m/z: 361 (M+, 100%).

n-(4-acetylphenyl)-4-(2-oxo-2- phenylethylamino)benzamide (66)Prepared by reacting 37 (3 g, 11.8 mmol) and H1 (2.35 g,



Melting point 243°C–245°C; IR 3,390, 3,369, 3,001, 1,666, 1,651, 1,323 cm-1; 1H-NMR (400 mHz, DMSO-d6):

δ 2.52 (s, 3H, CH3), 4.80 (s, 2H, CH

2), 6.76 (d, 2H, Ar-H,

J=8.6 Hz), 7.57 (t, 2H, Ar-H, J=7.6 Hz), 7.68 (t, 1H, Ar-H, J=7.4 Hz), 7.8 (d, 2H, Ar-H, J=8.6 Hz), 7.91 (m, 4H, Ar-H), 8.08 (d, 2H, Ar-H, J=7.4 Hz), 10.13 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 29.04, 52.09, 114.13, 121.73, 123.80, 130.55, 131.44, 131.68, 132.07, 133.99, 136.27,

137.64, 146.95, 154.12, 168.25, 198.71, 199.14; MS (EI)

m/z: 737 (M+, 100%).



11.8 mmol), to yield 3.1 g (70%) of 67 as light yellow

crystals. Melting point 242°C–244°C; IR 3,396, 3,338, 3,059, 1,666, 1,651, 1,330 cm-1; 1H-NMR (400 mHz,

DMSO-d6): δ 2.54 (s, 3H, CH3), 4.77 (s, 2H, CH

2),

6.16 (s, 1H, NH-Ar), 6.91 (s, 1H, Ar-H), 7.16 (d, 1H,

Ar-H, J=7.6 Hz), 7.24 (t, 1H, Ar-H, J=7.6 Hz), 7.58 (t, 2H, Ar-H, J=7.3 Hz), 7.67 (t, 1H, Ar-H, J=7.3 Hz), 7.93 (m, 4H, Ar-H), 8.08 (d, 2H, Ar-H, J=7.5 Hz), 10.40 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 25.60, 48.93, 110.63, 114.54, 115.04, 118.52, 127.03, 127.98, 128.40, 131.2,

132.75, 134.23, 134.8, 147.44, 165.86, 195.78; MS (EI)

m/z: 373 (M+, 100%).



11.8 mmol), to yield 2.5 g (68%) of 68 as off-white crys-

tals. Melting point 201°C–203°C; IR 3,369, 3,294, 3,072, 1,687, 1,643, 1,309 cm-1; 1H NMR (400 mHz, DMSO-d6):

δ 2.57 (s, 3H, CH3), 4.81 (d, 2H, CH

2, J=5.4 Hz), 6.59

(t, 1H, NH-Ar, J=5.3 Hz), 6.79 (d, 2H, Ar-H, J=8.7 Hz), 7.47 (t, 1H, Ar-H, J=7.9 Hz), 7.57 (t, 2H, Ar-H, J=7.6 Hz), 7.67 (m, 2H, Ar-H), 7.83 (d, 2H, Ar-H, J=8.7 Hz), 8.08 (m, 3H, Ar-H), 8.36 (s, 1H, Ar-H), 10.04 (s, 1H, CO-NH); 13C-NMR

(DMSO-d6): δ 29.38, 52.10, 114.15, 122.16, 123.94, 125.61, 127.27, 130.57, 131.54, 131.92, 136.31, 137.31, 139.80,

142.75, 153.97, 168.14, 198.81, 200.50; MS (EI) m/z: 373

(M+, 100%).

n-(4-acetylphenyl)-3-(2-oxo-2- phenylethylamino)benzamide (69)Prepared by reacting 40 (1.5 g, 5.9 mmol) and H1 (1.18 g,




3), 4.78 (s, 2H, CH

2), 6.16 (s, 1H, Ar-H), 6.92 (d,

1H, Ar-H, J=7.5 Hz), 7.18 (d, 1H, Ar-H, J=7 Hz), 7.22 (m, 2H, Ar-H), 7.49 (t, 1H, Ar-H, J=7.6 Hz), 7.57 (t, 2H, Ar-H, J=7 Hz), 7.68 (t, 2H, Ar-H, J=7.2 Hz), 8.06 (d, 1H, Ar-H, J=7.2 Hz), 8.09 (d, 2H, Ar-H, J=7.4 Hz), 8.37 (s, 1H, Ar-H), 10.28 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 27.25, 50.30, 111.92, 115.81, 116.31, 120.14, 123.96, 125.25,

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128.40, 129.33, 129.49, 134.11, 135.60, 136.03, 137.73,

140.19, 148.79, 166.94, 197.01, 198.21; MS (EI) m/z: 373

(M+, 100%).

ethyl 4-[4-(2-oxo-2-phenylethylamino) benzoylamino]benzoate (70)Prepared by reacting 41 (3 g, 10.6 mmol) and H1 (2.1 g,


10.6 mmol), to yield 1.7 g (43%) of 70 as light yellow

crystals. Melting point 212°C–213°C; IR 3,383, 3,061, 1,697, 1,681, 1,336 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 1.31 (t, 3H, CH

3, J=8 Hz), 4.27 (q, 2H, COO-CH

2, J=8 Hz), 4.81

(d, 2H, CH2-N-Ar, J=4 Hz), 6.62 (t, 1H, NH-Ar, J=4 Hz), 6.79

(d, 2H, Ar-H, J=8 Hz), 7.54 (t, 2H, Ar-H, J=8 Hz), 7.67 (t, 2H, Ar-H, J=8 Hz), 7.82 (d, 2H, Ar-H, J=8 Hz), 7.92 (s, 4H, Ar-H), 8.09 (d, 2H, Ar-H, J=8 Hz), 10.14 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 16.57, 52.11, 63.00, 114.15, 121.88, 123.83, 126.46, 130.58, 131.45, 132.09, 132.63, 136.28, 137.65,

146.96, 154.12, 168.10, 168.28, 198.72; MS (EI) m/z: 403

(M+, 100%).

ethyl 4-[3-(2-ixo-2-phenylethylamino) benzoylamino]benzoate (71)Prepared by reacting 42 (1.5 g, 5.3 mmol) and H1 (1.05 g,



Melting point 180°C–182°C; IR 3,408, 3,360, 2,981, 1,703, 1,654, 1,336 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 3.93 (s, 3H,CH

3), 4.94 (d, 2H, CH

2, J=5 Hz), 6.25 (t, 1H, NH-Ar,

J=5 Hz), 6.92 (m, 3H, Ar-H), 7.16 (d, 1H, Ar-H, J=7.2 Hz), 7.25 (d, 1H Ar-H, J=7.2 Hz), 7.57 (t, 2H, Ar-H, J=7 Hz), 7.7.67 (d, 2H, Ar-H, J=7.1 Hz), 8.18 (d, 2H, Ar-H, J=7 Hz), 10.23 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 21.22, 52.35, 58.71, 114.16, 124.49, 124.91, 125.61, 129.57, 131.82,

133.19, 133.66, 138.83, 139.69, 142.37, 153.72, 167.95,

197.95 ; MS (EI) m/z: 403 (M+, 100%).

ethyl 3-[4-(2-oxo-2-phenylethylamino) benzoylamino]benzoate (72)Prepared by reacting 43 (2 g, 7 mmol) and H1 (1.4 g,

7 mmol) in the presence of potassium carbonate (1 g,

7 mmol), to yield 1.35 g (48%) of 72 as light orange

crystals. Melting point 221°C–223°C; IR 3,379, 3,275, 3,049, 1,714, 1,645, 1,361 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 1.27 (t, 3H, CH3, J=8 Hz), 4.26 (q, 2H, COO-

CH2), 4.74 (s, 2H, CH

2-N-Ar), 6.51 (s, 1H, NH-Ar), 6.71

(s, 2H, Ar-H), 7.41 (s, 1H, Ar-H), 7.56 (m, 4H, Ar-H), 7.75

(s, 2H, Ar-H), 8.01 (s, 3H, Ar-H), 8.35 (s, 1H, Ar-H),

9.99 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 14.16, 49.45, 60.68, 111.45, 120.58, 121.28, 123.50, 124.48,

124.80, 127.88, 128.77, 129.23, 130.18, 133.23, 135.00,

140.08, 151.28, 165.40, 165.71, 196.10; MS (EI) m/z:

403 (M+, 100%).

ethyl 3-[3-(2-oxo-2-phenylethylamino) benzoylamino]benzoate (73)Prepared by reacting 44 (1.5 g, 5.3 mmol) and H1 (1.05 g,



Melting point 194°C–195°C; IR 3,365, 3,269, 3,068, 1,710, 1,645, 1,359 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 1.34 (t, 3H, CH

3, J=6.9 Hz), 4.34 (q, 2H, COO-CH

2, J=7 Hz), 4.79

(d, 2H, CH2-N-Ar, J=4.9 Hz), 6.16 (t, 1H, NH-Ar, J=5 Hz),

7.22 (m, 3H, Ar-H), 7.5 (t, 1H, Ar-H, J=7.8 Hz), 7.59 (t, 2H, Ar-H, J=7.3 Hz), 7.69 (d, 2H, Ar-H, J=7.3 Hz), 8.70 (d, 2H, Ar-H, J=7.8 Hz), 8.1 (d, 2H, Ar-H, J=7.4 Hz), 8.44 (s, 1H, Ar-H), 10.30 (s, 1H, CO-NH); 13C-NMR (DMSO-d6):

δ 14.12, 49.75, 60.70, 111.38, 115.27, 115.75, 120.71, 123.99, 124.62, 127.81, 128.74, 128.90, 130.22, 133.51,

135.05, 135.43, 139.60, 148.20, 165.59, 166.36, 196.43; MS

(EI) m/z: 403 (M+, 100%).

4-[2-(4-nitrophenyl)-2-oxoethylamino]- n-phenylbenzamide (74)Prepared by reacting 23 (1.4 g, 6.6 mmol) and 45 (1.6 g,


6.6 mmol), to yield 1.4 g (58%) of 74 as bright yellow

crystals. Melting point 210°C–212°C; IR 3,421, 3,402, 3,346, 3,062, 1,680, 1,653, 1,333, 1,520 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 4.87 (d, 2H, CH2, J=8 Hz), 6.60 (s, 1H, NH-Ar),

6.78 (d, 2H, Ar-H, J=8 Hz), 7.03 (t, 1H, Ar-H, J=8 Hz), 7.31 (t, 2H, Ar-H, J=12 Hz), 7.75 (d, 2H, Ar-H, J=8 Hz), 7.81 (d, 2H, Ar-H, J=8 Hz), 8.29 (d, 2H, Ar-H, J=8 Hz), 8.38 (d, 2H, Ar-H, J=8 Hz), 9.82 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 45.38, 106.74, 115.42, 117.21, 118.21, 119.11, 123.70, 124.41, 124.68, 134.95, 134.99, 145.41, 146.26, 160.49,

191.02; MS (EI) m/z: 376 (M+, 100%).

4-[2-(3-methoxyphenyl)-2-oxoethylamino]- n-phenylbenzamide (75)Prepared by reacting 23 (1.11 g, 5.2 mmol) and 46 (1.2 g,



Melting point 200°C–202°C; IR 3,379, 3,329, 3,051, 1,685, 1,647, 1,311, 1,267, 1,026 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 3.83 (s, 3H, CH3), 4.79 (d, 2H, CH

2, J=4 Hz),

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6.54 (t, 1H, NH-Ar, J=4 Hz), 6.78 (d, 2H, Ar-H, J=8 Hz), 7.03 (t, 1H, Ar-H, J=8 Hz), 7.25 (d, 1H, Ar-H, J=8 Hz), 7.30 (t, 2H, Ar-H, J=8 Hz), 7.48 (t, 1H, Ar-H, J=8 Hz), 7.57 (s, 1H, Ar-H), 7.69 (d, 1H, Ar-H, J=8 Hz), 7.77 (d, 2H, Ar-H, J=8 Hz), 7.80 (d, 2H, Ar-H, J=8 Hz), 9.83 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 52.25, 58.05, 114.13, 115.28, 122.16, 122.83, 122.99, 124.43, 125.60, 131.11, 131.63,

132.64, 139.04, 142.39, 153.79, 153.79, 162.13, 167.95,

198.65; MS (EI) m/z: 361 (M+, 100%).

4-[2-(4-methoxyphenyl)-2-oxoethylamino]- n-phenylbenzamide (76)Prepared by reacting 23 (1 g, 4.7 mmol) and 47 (1.08 g,


4.7 mmol), to yield 0.9 g (53%) of 76 as off-white crystals.

Melting point 206°C–208°C; IR 3,383, 3,282, 3,049, 1670, 1,641, 1,321, 1,029 cm-1; 1H NMR (400 mHz, DMSO-d6):

δ 3.88 (s, 3H, CH3), 4.73 (d, 2H, Ar-H, J=5 Hz), 6.4921

(t, 1H, NH-Ar, J=5 Hz), 6.77 (d, 2H, Ar-H, J=8.3 Hz), 7.05 (t, 1H, Ar-H, J=7.3 Hz), 7.1 (d, 2H, Ar-H, J=8.4 Hz), 7.32 (t, 2H, Ar-H, J=7.5 Hz), 7.77 (d, 2H, Ar-H, J=8.4 Hz), 7.8 (d, 2H, Ar-H, J=8.3 Hz), 8.09 (d, 2H, Ar-H, J=8.4 Hz), 9.81 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 49.07, 55.54, 111.39, 113.96, 120.11, 121.66, 122.87, 127.88, 128.38, 129.09,

130.20, 139.67, 151.67, 151.09, 163.42, 165.21, 194.33; MS

(EI) m/z: 361 (M+, 100%).

4-[2-(4-cyanophenyl)-2-oxoethylamino]- n-phenylbenzamide (77)Prepared by reacting 23 (1.89 g, 8.9 mmol) and H2 (2 g,




δ 4.85 (d, 2H, CH2, J=5.1 Hz), 6.59 (t, 1H, NH-Ar, J=4.1 Hz),

6.77 (d, 2H, Ar-H, J=8.3 Hz), 7.04 (t, 1H, Ar-H, J=7.3 Hz), 7.31 (t, 2H, Ar-H, J=7.1 Hz), 7.75 (m, 4H, Ar-H), 8.07 (d, 2H, Ar-H, J=7 Hz), 8.23 (d, 2H, Ar-H, J=7.8 Hz), 9.81 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 50.05, 111.35, 115.2, 120.04, 120.23, 123.5, 128.32, 128.48, 129.02, 132.39,

132.70, 139.9, 136.5, 150.90, 165.69, 195.50; MS (EI) m/z:

355 (M+, 100%).

4-[2-(2-methoxyphenyl)-2-oxoethylamino]- n-phenylbenzamide (78)Prepared by reacting 23 (1.85 g, 8.7 mmol) and H3 (2 g,


8.7 mmol), to yield 1.5 g (56%) of 78 as yellow crystals.


δ 3.96 (s, 3H, CH3), 4.57 (d, 2H, CH

2, J=5.6 Hz), 6.6 (t, 1H,

NH-Ar, J=5.4 Hz), 6.66 (d, 2H, Ar-H, J=8.6 Hz), 7.03 (t, 1H, Ar-H, J=7.1 Hz), 7.07 (t, 1H, Ar-H, J=7.3 Hz), 7.22 (d, 1H, Ar-H, J=8.3 Hz), 7.3 (t, 2H, Ar-H, J=7.8 Hz), 7.59 (t, 2H, Ar-H, J=7.7 Hz), 7.68 (d, 2H, Ar-H, J=7.6 Hz), 7.77 (m, 3H, Ar-H), 9.80 (s, 1H, CO-NH); 13C-NMR (DMSO-

d6): δ 53.37, 55.92, 111.20, 112.52, 120.10, 120.62, 121.66, 122.88, 125.77, 128.40, 129.17, 129.63, 134.23,

139.71, 151.18, 158.68, 165.25, 197.78; MS (EI) m/z: 361

(M+, 100%).

4-[2-(3-bromophenyl)-2-oxoethylamino]- n-phenylbenzamide (79)Prepared by reacting 23 (1.59 g, 7.5 mmol) and H4


(0.75 g, 7.5 mmol), to yield 0.9 g (40%) of 79 as light

yellow crystals. Melting point 200°C–203°C; IR 3,375, 3,319, 3,051, 1,687, 1,643, 1,319, 1,186 cm-1; 1H NMR

(400 mHz, DMSO-d6): δ 4.75 (d, 2H, CH2, J=8.5 Hz), 6.61

(t, 1H, NH-Ar, J=8.8 Hz), 6.78 (d, 2H, Ar-H, J=8 Hz), 7.03 (t, 1H, Ar-H, J=6.9 Hz), 7.3 (t, 2H, Ar-H, J=7.5 Hz), 7.52 (t, 1H, Ar-H, J=7.9 Hz), 7.76 (d, 2H, Ar-H, J=8.5 Hz), 7.81 (d, 2H, Ar-H, J=8 Hz), 7.87 (d, 1H, Ar-H, J=7.6 Hz), 8.07 (d, 1H, Ar-H, J=7.2 Hz), 8.24 (s, 1H, Ar-H), 9.85 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 52.35, 114.16, 122.5, 124.49, 124.91, 125.61, 129.57, 130.5, 131.82, 133.19,

133.66, 138.84, 139.69, 142.37, 153.72, 167.95, 197.95;

MS (EI) m/z: 399 (M+, 100%).

4-[2-(4-fluorophenyl)-2-oxoethylamino]- n-phenylbenzamide (80)Prepared by reacting 23 (1.96 g, 9.2 mmol) and H5 (2 g,



Melting point 222°C–224°C; IR 3,385, 3,072, 1,680, 1,643, 1,319, 1,193 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.78 (d, 2H, CH

2, J=4 Hz ), 6.54 (t, 1H, NH-Ar, J=4 Hz), 6.78 (d,

2H, Ar-H, J=8 Hz), 7.03 (t, 1H, Ar-H, J=8 Hz), 7.30 (t, 2H, Ar-H, J=8 Hz), 7.38 (t, 2H, Ar-H, J=8 Hz), 7.77 (d, 2H, Ar-H, J=8 Hz), 7.81 (d, 2H, Ar-H, J=8 Hz), 8.17 (t, 2H, Ar-H, J=8 Hz), 9.83 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 52.12, 114.13, 118.37, 118.58, 122.83, 124.46, 125.60, 131.10, 131.84,

133.58, 133.67, 134.41, 142.38, 153.76, 166.67, 167.95,

169.17, 197.45; MS (EI) m/z: 349 (M+, 100%).

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4-[2-(3-nitrophenyl)-2-oxoethylamino]- n-phenylbenzamide (81)Prepared by reacting 23 (2.61 g, 12.3 mmol) and H6


(0.62 g, 12.3 mmol), to yield 1.3 g (27%) of 81 as bright

yellow crystals. Melting point 201°C–203°C; IR 3,394, 3,072, 1,687, 1,645, 1,531, 1,350, 1,315 cm-1; 1H NMR

(400 mHz, DMSO-d6): δ 4.9 (d, 2H, CH2, J=3.6 Hz),

6.61 (s, 1H, NH-Ar), 6.78 (d, 2H, Ar-H, J=8.4 Hz), 7.04 (t, 1H, Ar-H, J=7.3 Hz), 7.3 (t, 2H, Ar-H, J=7.5 Hz), 7.73 (d, 2H, Ar-H, J=8.1 Hz), 7.77 (d, 2H, Ar-H, J=8.5 Hz), 7.87 (t, 1H, Ar-H, J=8 Hz), 8.51 (d, 2H, Ar-H, J=7.8 Hz), 8.76 (s, 1H, Ar-H), 9.82 (s, 1H, CO-NH); 13C-NMR (DMSO-d6):

δ 50.58, 112.21, 113.58, 120.93, 123.01, 123.73, 128.39, 129.14, 129.84, 130.00, 131.31, 134.87, 140.29, 148.77,

151.73, 166.01, 195.83; MS (EI) m/z: 376 (M+, 100%).

4-[2-(4-bromophenyl)-2-oxoethylamino]- n-phenylbenzamide (82)Prepared by reacting 23 (3 g, 14.1 mmol) and H7 (3.93 g,



Melting point 225°C–226°C; IR 3,390, 3,059, 1,678, 1,643, 1,319 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.77 (d, 2H, CH

2, J=5 Hz); 6.55 (t, 1H, NH-Ar, J=5 Hz); 6.74

(d, 2H, Ar-H, J=8.4 Hz); 7.05 (t, 1H, Ar-H, J=7.1 Hz); 7.3 (t, 2H, Ar-H, J=7.7 Hz); 7.73 (d, 2H, Ar-H, J=8.1 Hz); 7.77 (d, 2H, Ar-H, J=7.1 Hz); 7.78 (d, 2H, Ar-H, J=8.4 Hz); 8.01 (d, 2H, Ar-H, J=8.2 Hz); 9.82 (s,1H, CO-NH); 13C-NMR (DMSO-d6): δ 50.06, 112.02, 120.72, 122.30, 123.51, 128.49, 129.02, 129.38, 129.73, 134.20, 135.58, 140.27, 151.27,

151.70, 165.84, 196.75; MS (EI) m/z: 409 (M+, 100%).

4-[2-oxo-2-(4-trifluoromethylphenyl)ethylamino]- n-phenylbenzamide (83)Prepared by reacting 23 (1.53 g, 7.2 mmol) and H8 (2 g,




2), 6.60 (s, 1H, NH-Ar), 6.77 (s, 2H, Ar-H), 7.03

(s, 1H, Ar-H), 7.30 (s, 2H, Ar-H), 7.76 (s, 4H, Ar-H), 7.94 (s, 2H,

Ar-H), 8.27 (s, 2H, Ar-H), 9.81 (s, 1H, CO-NH); 13C-NMR

(DMSO-d6): δ 50.40, 111.99, 120.71, 120.89, 122.41, 123.48, 124.26 (C-F, J=1242 Hz), 126.24 (C-F, J=14.4 Hz), 128.95, 129.29, 129.68, 133.37 (C-F, J=139.12 Hz), 138.75, 140.19, 151.55, 165.80, 196.4194; MS (EI) m/z: 410 (M+, 100%).

4-[2-(4-chlorophenyl)-2-oxoethylamino]- n-phenylbenzamide (84)Prepared by reacting 23 (2.73 g, 15.4 mmol) and H9 (3.6 g,



Melting point 218°C–219°C; IR 3,390, 3,039, 1,680, 1,643, 1,321 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.79 (s, 2H, CH

2), 6.55 (s, 1H, NH), 6.77 (d, 2H, Ar-H, J=8 Hz), 7.05

(t, 1H, Ar-H, J=7.3 Hz), 7.32 (t, 2H, Ar-H, J=7.4 Hz), 7.65 (d, 2H, Ar-H, J=7.8 Hz), 7.61 (d, 2H, Ar-H, J=126.3 Hz), 7.79 (d, 2H, Ar-H, J=8.1 Hz), 8.1 (d, 2H, Ar-H, J=7.8 Hz), 9.84 (s, CO-NH); 13C-NMR (DMSO-d6): δ 52.18, 114.12, 122.86, 124.42, 125.66, 131.12, 131.57, 131.82, 132.50, 136.31,

141.19, 142.30, 153.73, 167.97, 198.01; MS (EI) m/z: 365

(M+, 100%).

n-(4-methoxyphenyl)-4-[2-(4-methoxyphenyl)- 2-oxoethylamino]benzamide (87)Prepared by reacting 33 (0.5 g, 2.1 mmol) and 47 (0.47 g,


2.1 mmol) and sodium iodide (0.32 g, 2.1 mmol), to yield

0.36 g (40%) of 87 as off-white crystals. Melting point

222°C–223°C; IR 3,354, 3,008, 1,664, 1,643, 1,321, 1,029 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 3.75 (s, 3H, CH

3), 3.88 (s, 3H, CH

3), 4.72 (d, 2H, CH

2, J=5 Hz), 6.45

(t, 1H, NH-Ar, J=4.7 Hz), 6.76 (d, 2H, Ar-H, J=8.6 Hz), 6.9 (d, 2H, Ar-H, J=9 Hz), 7.1 (d, 2H, Ar-H, J=8.8 Hz), 7.65 (d, 2H, Ar-H, J=8.9 Hz), 7.78 (d, 2H, Ar-H, J=8.6 Hz), 8.09 (d, 2H, Ar-H, J=8.8 Hz), 9.4 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 49.10, 55.11, 55.57, 111.40, 113.58, 113.98, 121.75, 121.81, 127.90, 128.94, 130.22, 132.76,

150.94, 155.07, 163.43, 164.86, 194.39; MS (EI) m/z: 391

(M+, 100%).

n-(3-chlorophenyl)-4-[2-(3-nitrophenyl)-2-oxoethylamino]benzamide (88)Prepared by reacting 31 (0.5 g, 2 mmol) and 45 (0.5 g,

2 mmol) in the presence of potassium carbonate (0.2 g,

2 mmol), to yield 0.24 g (29%) of 88 as bright yellow

crystals. Melting point 195°C–196°C; IR 3,402, 3,381, 3,057, 1,667, 1,666, 1,514, 1,350, 1,087 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 4.92 (s, 2H, CH2), 6.67 (s, 1H, NH-Ar), 6.8

(d, 2H, Ar-H, J=8.3 Hz), 7.09 (d, 1H, Ar-H, J=7.6 Hz), 7.33 (t, 1H, Ar-H, J=8 Hz), 7.68 (d, 1H, Ar-H, J=8 Hz), 7.78 (d, 2H, Ar-H, J=8.3 Hz), 7.88 (t, 1H, Ar-H, J=7.9 Hz), 7.95 (s, 1H, Ar-H), 8.51 (d, 2H, Ar-H, J=7.6 Hz), 8.77 (s, 1H, Ar-H), 9.96 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 50.40, 112.05,

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118.84, 119.92, 121.86, 122.87, 123.06, 128.24, 129.77,

130.65, 131.12, 133.33, 134.74, 136.73, 141.76, 148.60,

151.81, 165.96, 195.56; MS (EI) m/z: 410 (M+, 100%).

synthesis of anilinoketones and anilinoesters from α-bromoketones/esters (85, 86, 89–94)Amino-N-phenylbenzamide (one equivalent), potassium

carbonate (one equivalent), sodium iodide (one equivalent),

and α-bromoketone (one equivalent) were dissolved in dimethylformamide (20 mL) and the reaction mixture was

stirred for 8 hours at room temperature. The reaction contents

were then poured over water with stirring, and the mixture

was left until the product precipitated. The product was then

filtered, dried, and recrystallized from ethanol.

4-(2-oxo-2-p-tolylethylamino)- n-phenylbenzamide (85)Prepared by reacting 23 (2 g, 9.5 mmol) and 48 (1.6 g,


9.5 mmol) and sodium iodide (1.42 g, 9.5 mmol) to yield 1.6 g

(50%) of 85 as beige crystals. Melting point 224°C–226°C; IR 3,385, 3,323, 3,051, 1,678, 1,643, 1,325 cm-1; 1H NMR


CH2), 6.62 (s, 1H, NH-Ar), 6.86 (d, 2H, Ar-H, J=7.7 Hz),

7.15 (t, 1H, Ar-H, J=7.1 Hz), 7.41 (t, 2H, Ar-H, J=7.2 Hz), 7.48 (d, 2H, Ar-H, J=7.2 Hz), 7.85 (d, 2H, Ar-H, J=8 Hz), 7.89 (d, 2H, Ar-H, J=8 Hz), 8.09 (d, 2H, Ar-H, J=7.2 Hz), 9.93 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 23.85, 51.96, 114.11, 122.87, 124.34, 125.66, 130.64, 131.11, 131.84, 131.99,

135.12, 142.31, 146.78, 153.77, 168.01, 198.25; MS (EI)

m/z: 345 (M+, 100%).

4-(2-naphthalen-2-yl-2-oxoethylamino)- n-phenylbenzamide (86)Prepared by reacting 23 (3 g, 13.4 mmol) and 49 (2.75 g,


13.4 mmol) and sodium iodide (2.12 g, 13.4 mmol) to yield

2.75 g (51%) of 86 as light yellow crystals. Melting point

221°C–223°C; IR 3,373, 3,057, 1,672, 1,645, 1,315 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.95 (d, 2H, CH

2, J=5.2 Hz),

6.62 (t, 1H, NH-Ar, J=5.1 Hz), 6.82 (d, 2H, Ar-H, J=8.6 Hz), 7.04 (t, 1H, Ar-H, J=7.3 Hz), 7.31 (t, 2H, Ar-H, J=7.8 Hz), 7.76 (d, 2H, Ar-H, J=7.9 Hz), 7.81 (d, 2H, Ar-H, J=8.6 Hz), 8.03 (d, 1H, Ar-H, J=8 Hz), 8.07 (s, 2H, Ar-H), 8.15 (d, 1H, Ar-H, J=18.3 Hz), 9.83 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 52.22, 114.15, 122.83, 124.42, 125.61, 126.12, 129.71, 130.40, 131.11, 131.46, 131.85, 132.24, 132.51, 134.85,

134.95, 137.91, 142.38, 153.83, 167.95, 198.75; MS (EI)

m/z: 381 (M+, 100%).

Phenyl (4-phenylcarbamoylphenylamino)acetate (89)Prepared by reacting 23 (1.24 g, 5.9 mmol) and 50 (1 g,


5.9 mmol) and sodium iodide (0.88 g, 5.9 mmol), to yield 0.96 g

(47%) of 89 as white crystals. Melting point 202°C–204°C; IR 3,394, 3,323, 3,051, 1,749, 1,643, 1,317 cm-1; 1H NMR

(400 mHz, DMSO-d6): δ 4.31 (d, 2H, CH2, J=4 Hz), 6.75

(d, 2H, Ar-H, J=8 Hz), 6.82 (t, 1H, NH-Ar, J=4 Hz), 7.04 (t, 1H, Ar-H, J=6 Hz), 7.14 (d, 2H, Ar-H, J=8 Hz), 7.26 (t, 1H, Ar-H, J=8 Hz), 7.31 (t, 2H, Ar-H, J=8 Hz), 7.43 (t, 2H, Ar-H, J=6 Hz), 7.76 (d, 2H, Ar-H, J=8 Hz), 7.84 (d, 2H, Ar-H, J=8 Hz), 9.86 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 47.09, 113.92, 122.82, 124.31, 124.99, 125.66, 128.63, 131.14, 131.96, 132.25, 142.36, 153.02, 153.62, 167.94,

172.60; MS (EI) m/z: 347 (M+, 100%).

naphthalen-2-yl (4-phenylcarbamoylphenylamino)acetate (90)Prepared by reacting 23 (1.44 g, 6.8 mmol) and 51 (1.5 g,



1.17 g (44%) of 90 as light brown crystals. Melting point

233°C–234°C; IR 3,408, 3,350, 3,047, 1,759, 1,643, 1,336 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.38 (s, 2H, CH

2), 5.34 (s, 1H, NH-CO), 6.77 (d, 2H, Ar-H, J=8.7 Hz),

7.04 (t, 1H, Ar-H, J=7.3 Hz), 7.31 (m, 3H, Ar-H), 7.52 (m, 2H, Ar-H), 7.68 (s, 1H, Ar-H), 7.74 (d, 2H, Ar-H, J=7.7 Hz), 7.83 (d, 2H, Ar-H, J=8.7 Hz), 7.93 (t, 2H, Ar-H, J=9.2 Hz), 7.98 (d, 1H, Ar-H, J=9 Hz), 9.85 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 39.73, 106.54, 113.67, 115.42, 116.64, 117.58, 118.28, 121.17, 122.04, 122.74, 122.97, 123.74,

124.57, 124.72, 126.29, 128.54, 134.93, 143.28, 146.23,

160.54, 165.43; MS (EI) m/z: 397 (M+, 100%).

naphthalen-2-yl (3-phenylcarbamoylphenylamino)acetate (91)Prepared by reacting 24 (1.44 g, 6.8 mmol) and 51 (1.5 g,



1.6 g (60%) of 91 as off-white crystals. Melting point

169°C–170°C; IR 3,398, 3,317, 3,061, 1,753, 1,651, 1,321 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 4.36 (d, 2H, CH

2, J=6.2 Hz), 6.50 (t, 1H, NH-Ar, J=6.2 Hz), 6.9

(d, 1H, Ar-H, J=7.8 Hz), 7.09 (t, 1H, Ar-H, J=7.9 Hz), 7.21 (d, 1H, Ar-H, J=8.4 Hz), 7.22 (s, 1H, Ar-H), 7.29 (t, 1H,

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Ar-H, J=8.1 Hz), 7.33 (t, 2H, Ar-H, J=7.9 Hz), 7.36 (d, 1H, Ar-H, J=7.5 Hz), 7.53 (m, 2H, Ar-H), 7.69 (s, 1H, Ar-H), 7.78 (d, 2H, Ar-H, J=8 Hz), 7.9 (d, 1H, Ar-H, J=7.7 Hz), 7.95 (d, 1H, Ar-H, J=7.6 Hz), 7.98 (d, 1H, Ar-H, J=9.2 Hz), 10.13 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 44.79, 111.31, 115.20, 115.66, 118.38, 120.32, 121.35, 123.48,

125.85,126.72, 127.42, 127.67, 128.52, 128.92, 129.92,

130.99, 133.25, 135.93, 139.25, 148.01, 148.04, 166.11,

170.44; MS (EI) m/z: 397 (M+, 75%).

naphthalen-2-yl [4-(4-chlorophenylcarbamoyl)phenylamino]acetate (92)Prepared by reacting 26 (1.68 g, 6.8 mmol) and 51 (1.5 g,





NH-Ar), 6.92 (d, 1H, Ar-H, J=6.7 Hz), 7.22 (s, 2H, Ar-H), 7.3 (t, 2H, Ar-H, J=8.3 Hz), 7.42 (d, 2H, Ar-H, J=8 Hz), 7.54 (s, 2H, Ar-H), 7.84 (d, 2H, Ar-H, J=7.9 Hz), 7.91 (d, 2H, Ar-H, J=7.4 Hz), 7.96 (d, 2H, Ar-H, J=6.9 Hz), 10.29 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 43.98, 110.53, 114.55, 114.88, 117.57, 120.52, 121.02, 125.04, 125.92, 126.60, 126.86,

127.64, 128.18, 128.60, 130.18, 134.83, 137.41, 147.20,

147.26, 159.02, 165.44; MS (EI) m/z: 431 (M+, 100%).

naphthalen-2-yl (4-p-tolylcarbamoylphenylamino)acetate (93)Prepared by reacting 30 (1.54 g, 6.8 mmol) and 51 (1.5 g,




(400 mHz, DMSO-d6): δ 2.27 (s, 3H, CH3), 4,36 (s, 2H,

CH2), 6.51 (s, 1H, NH-Ar), 6.89 (s, 1H, Ar-H), 7.15 (s, 2H,

Ar-H), 7.21 (s, 2H, Ar-H), 7.29 (d, 2H, Ar-H, J=11.1 Hz), 7.53 (s, 2H, Ar-H), 7.65 (s, 3H, Ar-H), 7.93 (m, 3H, Ar-H),

10.07 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 20.98, 45.35, 111.81, 115.70, 116.19, 118.91, 120.92, 121.87,

126.38, 127.26, 127.95, 128.20, 129.45, 129.94, 131.52,

132.97, 133.78, 136.52, 137.24, 148.55, 166.44, 170.98; MS

(EI) m/z: 411 (M+, 100%).

naphthalen-2-yl [4-(3-chlorophenylcarbamoyl)phenylamino]acetate (94)Prepared by reacting 32 (1.68 g, 6.8 mmol) and 51 (1.5 g,





(t, 1H, NH-Ar, J=5.4 Hz), 6.92 (d, 1H, Ar-H, J=8.6 Hz), 7.08 (d, 1H, Ar-H, J=8.6 Hz), 7.13 (m, 2H, Ar-H), 7.22 (m, 2H, Ar-H), 7.3 (t, 1H, Ar-H, J=8.7 Hz), 7.36 (t, 1H, Ar-H, J=13.3 Hz), 7.36 (m, 2H, Ar-H), 7.51 (m, 2H, Ar-H), 7.67 (m, 2H, Ar-H), 7.93 (m, 3H, Ar-H), 10.35 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 40.05, 106.60, 110.76, 110.98, 113.69, 113.86, 114.93, 116.64, 118.46, 121.15, 122.02,

122.71, 122.97, 124.31, 124.71, 125.55, 128.20, 128.54,

130.80, 136.04, 143.38, 161.71, 165.72; MS (EI) m/z: 431

(M+, 100%).

synthesis of anilinoalcohols (95–120)One equivalent of anilinoketone was dissolved in 20 mL of

methanol, to which a 1.2 equivalent of sodium borohydride

was added. The round bottom flask was fitted with a bent dry-

ing tube filled with silica gel (blue). The reaction was stirred

at room temperature for 2 hours. The methanol was then

evaporated under vacuum and the residue was dissolved in

50 mL of dichloromethane and washed with 30 mL of water,

then with 30 mL of 1 M HCl solution, and again with 30 mL

of water. The dichloromethane layer was then dried using

magnesium sulfate filtered and evaporated under vacuum.

The product was recrystallized from ethyl acetate/hexane.

4-(2-hydroxy-2-phenylethylamino)- n-phenylbenzamide (95)Prepared by reducing 52 (0.5 g, 1.5 mmol) using sodium

borohydride (0.026 g, 1.8 mmol), to yield 0.24 g (48%) of

95 as yellow crystals. Melting point 150°C–152°C; IR 3,394, 3,369, 3,348, 3,032, 1,606, 1,321 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 3.21 (m, 1H, CH2-N-Ar), 3.28 (m, 1H, CH

2-

N-Ar), 4.76 (d,1H, CH-O, J=3.3 Hz), 5.56 (s, 1H, OH), 6.3 (t, 1H, NH-Ar, J=5.1 Hz), 6.68 (d, 2H, Ar-H, J=8.4 Hz), 7.04 (t, 1H, Ar-H, J=7 Hz), 7.31 (m, 5H, Ar-H), 7.42 (d, 2H, Ar-H, J=7.6 Hz), 7.75 (t, 4H, Ar-H, J=9.5 Hz), 9.79 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 46.09, 66.07, 106.26, 115.40, 116.38, 118.14, 121.32, 122.31, 123.31, 123.69, 124.53, 135.04,

139.21, 146.86, 160.52; MS (EI) m/z: 333 (M+, 100%).

4-(2-hydroxy-2-phenylethylamino)- n-p-tolylbenzamide (96)Prepared by reducing 54 (0.5 g, 1.5 mmol) using sodium

borohydride (0.07 g, 1.8 mmol) to yield 0.35 g (70%) of 96 as

white crystals. Melting point 132°C–133°C; IR 3,381, 3,367,

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3,037, 1,614, 1,346 cm-1; 1H NMR (400 mHz, DMSO-d6):

δ 2.27 (s, 3H, CH3), 3.21 (m, 1H, CH

2-N-Ar), 3.29 (m, 1H,

CH2-N-Ar), 4.76 (d, 1H, CH-O, J=3.3 Hz), 5.55 (d, 1H, OH,

J=3.8 Hz), 6.32 (s, 1H, NH-Ar), 6.69 (d, 2H, Ar-H, J=8.4 Hz), 7.11 (d, 2H, Ar-H, J=8 Hz), 7.27 (t, 1H, Ar-H, J=7 Hz), 7.36 (t, 2H, Ar-H, J=7.3 Hz), 7.63 (d, 2H, Ar-H, J=8 Hz), 7.76 (d, 2H, Ar-H, J=8.3 Hz), 9.72 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 15.70, 46.08, 66.04, 106.24, 115.44, 116.46, 121.30, 122.30, 123.30, 124.09, 124.43, 127.02, 132.45,

139.19, 146.74, 160.34; MS (EI) m/z: 348 (M+, 100%).

n-(4-chlorophenyl)-4-(2-hydroxy-2-phenylethylamino)benzamide (97)Prepared by reducing 58 (0.5 g, 1.4 mmol) using sodium boro-

hydride (0.062 g, 1.68 mmol), to yield 0.34 g (68%) of 97 as

white crystals. Melting point 169°C–171°C; IR 3,562, 3,410, 3,385, 3,030, 1,643, 1,328, 1,087 cm-1; 1H NMR (400 mHz,


2-

N-Ar), 4.77 (t, 1H, CH-O, J=3.4 Hz), 5.57 (d, 1H, OH, J=4.2 Hz), 6.39 (t, 1H, NH-Ar, J=5.3 Hz), 6.7 (d, 2H, Ar-H, J=8.5 Hz), 7.27 (t, 1H, Ar-H, J=7.1 Hz), 7.36 (m, 4H, Ar-H), 7.55 (d, 2H, Ar-H, J=7.8 Hz), 7.78 (d, 2H, Ar-H, J=8.6 Hz), 7.81 (d, 2H, Ar-H, J=8.8 Hz), 9.93 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 49.93, 69.95, 110.15, 119.86, 120.73, 125.20, 125.60, 126.21, 127.20, 127.64, 128.49, 137.90, 143.06,

150.89, 164.49; MS (EI) m/z: 367 (M+, 100%).

n-(3-chlorophenyl)-4-(2-hydroxy-2-phenylethylamino)benzamide (98)Prepared by reducing 60 (0.5 g, 1.4 mmol) using sodium

borohydride (0.062 g, 1.68 mmol) to yield 0.2 g (40%) of

98 as white crystals. Melting point 181°C–182°C; IR 3,410, 3,338, 3,240, 3,028, 1,651, 1,311, 1,089 cm-1; 1H NMR

(400 mHz, DMSO-d6): δ 3.2 (m, 1H, CH2-N-Ar), 3.29

(m, 1H, CH2-N-Ar), 4.78 (s, 1H, CH-O), 5.54 (s, 1H, OH),

5.88 (t, 1H, NH-Ar, J=5.2 Hz), 6.86 (d, 1H, Ar-H, J=7.9 Hz), 7.12 (m, 2H, Ar-H), 7.22 (t, 1H, Ar-H, J=7.8 Hz), 7.26 (t, 2H, Ar-H, J=7.4 Hz), 7.36 (t, 2H, Ar-H, J=7.4 Hz), 7.41 (m, 4H, Ar-H), 7.81 (d, 2H, Ar-H, J=8.8 Hz), 10.22 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.28, 70.83, 110.99, 114.92, 115.56, 121.88, 126.09, 127.07, 127.12, 128.09, 128.50,

128.93, 135.60, 138.29, 144.29, 148.78, 166.46; MS (EI)

m/z: 367 (M+, 100%).

4-(2-hydroxy-2-phenylethylamino)- n-(4-methoxyphenyl)benzamide (99)Prepared by reducing 62 (0.5 g, 1.4 mmol) using sodium


99 as white crystals. Melting point 165°C–166°C; IR 3,408, 3,361, 3,331, 3,043, 1,612, 1,313, 1,246, 1,031 cm-1; 1H NMR


(m, 1H, CH2-N-Ar), 3.18 (s, 3H, CH

3), 4.75 (m, 1H, CH-O),

5.57 (d, 1H, OH, J=4.3 Hz), 6.38 (t, 1H, NH-Ar, J=5.5 Hz), 6.68 (d, 2H, Ar-H, J=8.6 Hz), 6.9 (d, 2H, Ar-H, J=8.9 Hz), 7.27 (t, 1H, Ar-H, J=7.5 Hz), 7.36 (t, 2H, Ar-H, J=7.5 Hz), 7.42 (d, 2H, Ar-H, J=7.4 Hz), 7.64 (d, 2H, Ar-H, J=8.9 Hz), 7.76 (d, 2H, Ar-H, J=8.6 Hz), 9.70 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.31, 55.65, 71.30, 111.50, 114.12, 121.70, 122.34, 126.55, 127.58, 128.57, 129.62, 133.25, 144.40, 151.93,

155.61, 165.48; MS (EI) m/z: 363 (M+, 100%).


borohydride (0.063 g, 1.68 mmol) to yield 0.28 g (56%)

of 100 as yellow oil. It was purified using preparative thin

layer chromatography before characterization. IR 3,408,

3,360, 3,000, 1,651, 1,325, 1,039 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 3.21 (s, 1H, CH2-N-Ar), 3.32 (s, 1H, CH

2-

N-Ar), 3.73 (s, 3H, CH3), 4.75 (s, 1H, CH-O), 5.53 (s, 1H,

OH), 6.32 (s, 1H, NH-Ar), 6.61 (s, 1H, Ar-H), 6.68 (s, 2H,



Ar-H), 9.97 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.28, 55.43, 71.26, 106.22, 108.91, 111.46, 112.82, 121.55, 126.55,

127.56, 128.55, 129.69, 129.76, 141.17, 144.82, 152.14,

159.85, 165.77; MS (EI) m/z: 363 (M+, 97%).

n-[3-(1-hydroxyethyl)phenyl]-4-(2-hydroxy- 2-phenylethylamino)benzamide (101)Prepared by reducing 68 (0.5 g, 1.6 mmol) using sodium

borohydride (0.144 g, 3.84 mmol), to yield 0.39 g (78%)

of 101 as light yellow oil. It was purified using prepara-

tive thin layer chromatography before characterization. IR

3,344, 2,954, 1,626, 1,319, 1,083 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 1.36 (s, 3H, CH3), 3.24 (m, 1H, CH

2-N-Ar),

3.31 (m, 1H, CH2-N-Ar), 4.71 (s, 1H, CH-O), 4.79 (s, 1H,

CH-O), 5.19 (s, 1H, OH), 5.59 (s, 1H, OH), 6.35 (s, 1H, NH),

6.71 (d, 1H, Ar-H, J=8.4 Hz), 7.04 (d, 2H, Ar-H, J=7 Hz), 7.26 (m, 2H, Ar-H), 7.37 (t, 2H, Ar-H, J=7.4 Hz), 7.45 (d, 2H, Ar-H, J=7.4 Hz), 7.68 (d, 1H, Ar-H, J=7.6 Hz), 7.77 (s, 1H, Ar-H), 7.82 (d, 2H, Ar-H, J=8.4 Hz), 9.80 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 21.20, 46.12, 63.47, 66.07, 106.25, 112.59, 113.75, 115.31, 116.43, 121.33, 122.31, 123.27,

123.31, 124.52, 134.80, 139.21, 143.03, 146.83, 160.45; MS

(EI) m/z: 377 (M+, 100%).

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ethyl 3-[4-(2-hydroxy-2-phenylethylamino)benzoylamino]benzoate (102)Prepared by reducing 70 (0.5 g, 1.2 mmol) using sodium


102 as white crystals. Melting point 163°C–165°C; IR 3,456, 3,396, 3,350, 2,937, 1,681, 1,319 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 1.32 (t, 3H, CH3, J=6.8 Hz), 3.22 (m, 1H, CH

2-

N-Ar), 3.30 (m, 1H, CH2-N-Ar), 4.29 (q, 2H, CH

2, J=6.9 Hz),

4.77 (s, 1H, CH-O), 5.57 (s, 1H, OH), 6.44 (s, 1H, NH-Ar),

6.71 (d, 2H, Ar-H, J=8 Hz), 7.27 (t, 1H, Ar-H, J=6.9 Hz), 7.35 (t, 2H, Ar-H, J=7 Hz), 7.43 (d, 2H, Ar-H, J=7.1 Hz), 7.8 (d, 2H, Ar-H, J=8 Hz), 7.93 (s, 4H, Ar-H), 10.12 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 14.74, 60.85, 71.31, 111.52, 119.71, 120.96, 121.00, 124.28, 126.57, 127.57,

128.56, 130.04, 130.47, 144.42, 144.85, 152.44, 165.96,

166.09; MS (EI) m/z: 405 (M+, 100%).

3-(2-hydroxy-2-phenylethylamino)- n-phenylbenzamide (103)Prepared by reducing 53 (0.5 g, 1.5 mmol) using sodium


103 as beige crystals. Melting point 142°C–143°C; IR 3,514, 3,352, 3,336, 3,032, 1,651, 1,327 cm-1; 1H NMR (400 mHz,


2-

N-Ar), 4.80 (m, 1H, CH-O), 5.54 (d, 1H, OH, J=4.4 Hz), 5.83 (t, 1H, NH-Ar, J=5.2 Hz), 6.48 (d, 1H, Ar-H, J=7.5 Hz), 7.09 (t, 1H, Ar-H, J=7.4 Hz), 7.13 (m, 2H, Ar-H), 7.21 (t, 1H, Ar-H, J=7.9 Hz), 7.26 (t, 1H, Ar-H, J=7.4 Hz), 7.34 (m, 4H, Ar-H), 7.43 (d, 2H, Ar-H, J=7.2 Hz), 7.75 (d, 2H, Ar-H, J=7.6 Hz), 10.08 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.75, 71.30, 111.49, 115.43, 115.92, 120.90, 124.04, 126.55, 127.54, 128.56, 129.06, 129.37, 136.34, 139.73,

144.53, 149.18, 166.83; MS (EI) m/z: 333 (M+, 100%).

3-(2-hydroxy-2-phenylethylamino)- n-p-tolylbenzamide (104)Prepared by reducing 55 (0.5 g, 1.5 mmol) using sodium


104 as beige crystals. Melting point 143°C–144°C; IR 3,348, 3,332, 3,030, 1,651, 1,319 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 2.30 (s, 3H, CH3), 3.21 (m, 1H, CH

2-N-Ar),

3.30 (m, 1H, CH2-N-Ar), 4.79 (s, 2H, CH-O), 5.56 (s, 1H,

OH), 5.81 (s, 1H, NH-Ar), 6.85 (d, 1H, Ar-H, J=7.7 Hz), 7.15 (m, 4H, Ar-H), 7.23 (t, 1H, Ar-H, J=7.8 Hz), 7.29 (t, 1H, Ar-H, J=7 Hz), 7.38 (t, 2H, Ar-H, J=7.4 Hz), 7.45 (d, 2H, Ar-H, J=7.5 Hz), 7.66 (d, 2H, Ar-H, J=8.2 Hz), 10.02 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 20.96, 51.73, 71.29, 111.41, 115.37, 115.81, 120.91, 126.53, 127.52,

128.54, 129.32, 129.43, 132.97, 136.38, 137.18, 144.52,

149.16, 166.61; MS (EI) m/z: 348 (M+, 100%).

3-(2-hydroxy-2-phenylethylamino)- n-m-tolylbenzamide (105)Prepared by reducing 57 (0.5 g, 1.5 mmol) using sodium


105 as yellow oil. This was purified using preparative thin

layer chromatography before characterization. IR 3,296,

3,028, 2,918, 1,651, 1,311 cm-1; 1H NMR (400 mHz, DMSO-

d6): δ 2.08 (s, 3H, CH3), 3.19 (s, 1H, CH

2-N-Ar), 3.29 (s,

1H, CH2-N-Ar), 4.76 (s, 1H, CH-O), 5.5 (s, 1H, OH), 5.81

(s, 1H, NH-Ar), 6.68 (s, 1H, Ar-H), 6.83 (s, 1H, Ar-H),

7.11 (s, 2H, Ar-H), 7.19 (s, 2H, Ar-H), 7.26 (s, 1H, Ar-H), 7.35

(s, 2H, Ar-H), 7.42 (s, 2H, Ar-H), 7.54 (s, 1H, Ar-H),

7.59 (s, 1H, Ar-H), 9.74 (s, 1H, CO-NH); 13C-NMR

(DMSO-d6): δ 21.71, 51.77, 71.28, 111.43, 115.36, 115.86, 118.03, 121.37, 124.64, 126.55, 127.49, 128.53, 128.86,

129.29, 138.14, 144.62, 149.21, 166.77; MS (EI) m/z: 348

(M+, 100%).

n-(4-chlorophenyl)-3-(2-hydroxy- 2-phenylethylamino)benzamide (106)Prepared by reducing 59 (0.5 g, 1.4 mmol) using sodium


of 106 as white crystals. Melting point 175°C–177°C; IR 3,336, 3,028, 1,651, 1,334, 1,089 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 3.18 (m, 1H, CH2-N-Ar), 4.77 (t, 1H, CH-O,

J=3.7 Hz), 5.48 (d, 1H, OH, J=4.2 Hz), 5.82 (t, 1H, NH-Ar, J=5.6 Hz), 6.84 (d, 1H, Ar-H, J=8 Hz), 7.10 (m, 2H, Ar-H), 7.21 (t, 1H, Ar-H, J=7.8 Hz), 7.26 (t, 1H, Ar-H, J=7.1 Hz), 7.38 (m, 6H, Ar-H), 7.8 (d, 2H, Ar-H, J=8.8 Hz), 10.18 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.78, 71.32, 111.50, 115.37, 116.01, 122.31, 126.56, 127.50, 128.53, 128.95,

129.35, 136.11, 138.81, 144.61, 149.27, 166.88; MS (EI)

m/z: 367 (M+, 100%).

n-(3-chlorophenyl)-3-(2-hydroxy-2-phenylethylamino)benzamide (107)Prepared by reducing 61 (0.5 g, 1.4 mmol) using sodium


107 as yellow oil. This was purified using preparative thin

layer chromatography before characterization. IR 3,305, 3,282,

3,263, 2,918, 1,643, 1,311, 1,060 cm-1; 1H NMR (400 mHz,


2-

N-Ar), 4.77 (s, 1H, CH-O), 5.5 (d, 1H, OH, J=4.5 Hz), 5.86 (d, 1H, NH-Ar, J=4.9 Hz), 6.85 (d, 1H, Ar-H, J=5.7 Hz), 7.13 (m, 3H, Ar-H), 7.21 (t, 1H, Ar-H, J=6.7 Hz), 7.26 (d, 1H, Ar-H,

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al-Balas et al

J=6.8 Hz), 7.34 (m, 3H, Ar-H), 7.38 (d, 2H, Ar-H, J=7.9 Hz), 7.69 (d, 3H, Ar-H, J=5.8 Hz), 7.95 (s, 1H, Ar-H), 10.22 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.75, 71.29, 111.46, 115.36, 116.11, 119.07, 120.13, 123.62, 126.55, 127.09,

128.53, 129.24, 130.75,133.38, 135.95, 141.32, 144.60,

149.27, 167.05; MS (EI) m/z: 367 (M+, 100%).



108 as white crystals. Melting point 153°C–155°C; IR 3,406, 3,334, 3,250, 3,028, 1,649, 1,334, 1,234, 1,035 cm-1; 1H NMR


(m, 1H, CH2-N-Ar), 3.74 (s, 3H CH

3), 4.77 (s, 2H, CH-O),

5.50 (s, 1H, OH), 5.79 (s, 1H, NH-Ar), 6.82 (d, 1H, Ar-H,

J=7.4 Hz), 6.91 (d, 2H, Ar-H, J=8.3 Hz), 7.11 (m, 2H, Ar-H), 7.19 (t, 2H, Ar-H, J=7.7 Hz), 7.26 (t, 1H, Ar-H, J=7 Hz), 7.35 (t, 2H, Ar-H, J=7.1 Hz), 7.42 (d, 2H, Ar-H, J=7.1 Hz), 7.64 (d, 2H, Ar-H, J=8.3 Hz), 9.93 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.80, 55.68, 71.29, 111.41, 114.18, 115.30, 115.75, 122.45, 126.56, 127.50, 128.53, 129.26, 132.89,

136.46, 144.63, 149.21, 155.91, 166.32; MS (EI) m/z: 363

(M+, 54%).



109 as light brown oil. This was purified using preparative

thin layer chromatography before characterization. IR 3,340,

3,288, 3,030, 1,645, 1,332, 1,047 cm-1; 1H NMR (400 mHz,


2-

N-Ar), 4.78 (m, 1H, CH-O), 5.51 (d, 1H, OH, J=4.4 Hz), 5.83 (t, 1H, NH-Ar, J=5.7 Hz), 6.67 (dd, 1H, Ar-H, J=8.2, 3.3 Hz), 6.85 (d, 1H, Ar-H, J=7.7 Hz), 7.11 (d, 1H, Ar-H, J=7.8 Hz), 7.13 (s, 1H, Ar-H), 7.24 (m, 3H, Ar-H), 7.35 (m, 4H, Ar-H),

7.43 (d, 2H, Ar-H, J=7.3 Hz), 10.04 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.77, 55.49, 71.30, 106.50, 109.43, 111.48, 113.03, 115.34, 115.89, 126.32, 127.51, 128.54,

129.31, 129.80, 136.38, 141.03, 144.63, 149.23, 159.90,

166.82; MS (EI) m/z: 363 (M+, 100%).

n-[4-(1-hydroxyethyl)phenyl]-3-(2-hydroxy- 2-phenylethylamino)benzamide (110)Prepared by reducing 67 (0.5 g, 1.6 mmol) using sodium


110 as light brown oil. This was purified using preparative

thin layer chromatography before characterization. IR

3,309, 3,296, 3,277, 2,924, 1,654, 1,321 cm-1; 1H NMR


(m, 1H, CH2-N-Ar), 3.27 (m, 1H, CH

2-N-Ar), 4.68 (m,

1H, CH-OH), 4.76 (m, 1H, CH-OH), 5.09 (d, 1H, OH,

J=4.2 Hz), 5.51 (d, 1H, OH, J=4.2 Hz), 5.82 (s, 1H, NH-Ar), 6.82 (d, 1H, Ar-H, J=8.1 Hz), 7.09 (s, 1H, Ar-H), 7.11 (d, 1H, Ar-H, J=5.6 Hz), 7.19 (t, 1H, Ar-H, J=7.8 Hz), 7.25 (t, 1H, Ar-H, J=7.3 Hz), 7.28 (d, 2H, Ar-H, J=8.6 Hz), 7.34 (t, 2H, Ar-H, J=7.5 Hz), 7.41 (d, 2H, Ar-H, J=7.2 Hz), 7.67 (d, 2H, Ar-H, J=8.5 Hz), 10.02 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 17.85, 29.83, 55.18, 71.67, 74.68, 114.85, 118.75, 119.21, 123.97, 129.31, 129.95, 130.90,

131.93, 132.69, 139.80, 141.62, 146.42, 148.02, 152.61,

170.00; MS (EI) m/z: 377 (M+, 100%).

4-[2-hydroxy-2-(3-methoxyphenyl)ethylamino]- n-phenylbenzamide (111)Prepared by reducing 79 (0.5 g, 1.4 mmol) using sodium


of 111 as white crystals. Melting point 126°C–127°C; IR 3,417, 3,369, 3,340, 3,049, 1,631, 1,316, 1,055 cm-1; 1H

NMR (400 mHz, DMSO-d6): δ 3.22 (m, 1H, CH2-N-Ar),

3.31 (m, 1H, CH2-N-Ar), 4.75 (d, 1H, CH-O, J=3.6 Hz), 5.57

(d, 1H, OH, J=4.3 Hz), 6.34 (t, 2H, NH-Ar, J=5.2 Hz), 6.71 (d, 2H, Ar-H, J=8.5 Hz), 6.84 (d, 1H, Ar-H, J=8 Hz), 7.00 (s, 2H, Ar-H), 7.05 (t, 1H, Ar-H, J=7.3 Hz), 7.26 (d, 1H, Ar-H, J=8 Hz), 7.32 (t, 2H, Ar-H, J=7.8 Hz), 7.78 (t, 4H, Ar-H, J=8.3 Hz), 9.81 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.26, 55.46, 71.22, 111.52, 112.13, 112.98, 118.77, 120.66, 121.60, 123.41, 128.94, 129.61, 129.78, 140.25, 146.15,

152.09, 159.68, 165.78; MS (EI) m/z: 363 (M+, 100%).





2-

N-Ar), 3.74 (s, 3H, CH3), 4.7 (d, 1H, CH-O, J=3.1 Hz), 5.42

(d, 1H, OH, J=2.8 Hz), 6.26 (s, 1H, NH-Ar), 6.68 (d, 2H, Ar-H, J=8 Hz), 6.91 (d, 2H, Ar-H, J=7.8 Hz), 7.03 (t, 1H, Ar-H, J=7.2 Hz), 7.31 (m, 4H, Ar-H), 7.76 (m, 4H, Ar-H), 9.77 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 51.38, 55.56, 70.85, 111.45, 113.96, 120.63, 121.53, 123.38, 127.72,

128.94, 129.78, 136.47, 140.29, 152.13, 158.91, 165.76; MS

(EI) m/z: 363 (M+, 100%).

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of 113 as yellow crystals. Melting point 140°C–142°C; IR 3,400, 3,323, 3,057, 1,643, 1,321, 1,051 cm-1; 1H

NMR (400 mHz, DMSO-d6): δ 2.95 (s, 1H, CH2-N-Ar),

3.16 (s, 1H, CH2-N-Ar), 3.88 (s, 3H, CH

3-O-Ar), 5.09

(s, 1H, CH-O), 5.36 (s, 1H, OH), 6.50 (s, 1H, NH-Ar),

6.75 (d, 2H, CH2, J=6.8 Hz), 7.02 (m, 3H,Ar-H), 7.25

(d, 1H, Ar-H, J=6.6 Hz), 7.32 (t, 2H, Ar-H, J=7.3 Hz), 7.51 (d, 1H, Ar-H, J=6.2 Hz), 7.77 (d, 2H, Ar-H, J=8.2 Hz), 7.8 (d, 2H, Ar-H, J=8.4 Hz), 9.79 (s, CO-NH); 13C-NMR (DMSO-d6): δ 54.54, 58.91, 64.33, 109.60, 110.05, 119.26, 119.49, 120.01, 122.00, 125.45, 127.13, 127.58, 128.41,

130.93, 138.95, 150.87, 154.75, 164.43; MS (EI) m/z: 363

(M+, 100%).

4-[2-(3-bromophenyl)-2-hydroxyethylamino]- n-phenylbenzamide (114)Prepared by reducing 83 (0.5 g, 1.3 mmol) using sodium


of 114 as white crystals. Melting point 157°C–159°C; IR 3,375, 3,350, 3,061, 1,614, 1,321, 1,053 cm-1; 1H NMR

(400 mHz, DMSO-d6): δ 3.22 (d, 1H, CH2-N-Ar, J=18.2 Hz),

3.35 (d, 1H, CH2-N-Ar, J=19.8 Hz), 4.77 (d, 1H, CH-O,

J=4.4 Hz), 5.72 (s, 1H, OH), 6.36 (s, 1H, NH-Ar), 6.71 (d, 2H, Ar-H, J=7.9 Hz), 7.04 (t, 1H, Ar-H, J=6.8 Hz), 7.32 (t, 3H, Ar-H, J=7.6 Hz), 7.42 (d, 1H, Ar-H, J=7.4 Hz), 7.47 (d, 1H, Ar-H, J=7.6 Hz), 7.62 (s, 1H, Ar-H), 7.77 (t, 4H, Ar-H, J=7.6 Hz), 9.80 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 45.75, 65.40, 106.30, 115.40, 116.40, 116.45, 116.79, 118.14,

120.49, 123.70, 124.10, 124.51, 125.11, 125.50, 135.02,

142.08, 146.79, 160.49; MS (EI) m/z: 412 (M+, 100%).

4-[2-(4-fluorophenyl)-2-hydroxyethylamino]- n-phenylbenzamide (115)Prepared by reducing 84 (0.5 g, 1.4 mmol) using sodium




2-

N-Ar), 4.77 (s, 1H, CH-O), 5.62 (s, 1H, OH), 6.34 (s, 1H,

NH-Ar), 6.69 (d, 2H, Ar-H, J=8.4 Hz), 7.04 (t, 1H, Ar-H, J=7.1 Hz), 7.17 (t, 2H, Ar-H, J=8.7 Hz), 7.31 (t, 2H, Ar-H, J=7.6 Hz), 7.46 (t, 2H, Ar-H, J=6.1 Hz), 7.77 (t, 4H, Ar-H, J=6.9 Hz), 9.80 (s, 1H,CO-NH); 13C-NMR (DMSO-d6): δ 49.86, 69.31, 110.14, 113.88 (C-F, J=83.8 Hz), 119.31,

120.22, 122.07, 127.15 (C-F, J=31.9 Hz), 127.60, 128.42, 138.89, 139.07 (C-F, J=138.3 Hz),150.73, 160.49 (C-F, J=963 Hz) 164.42; MS (EI) m/z: 351 (M+, 100%).

4-[2-hydroxy-2-(3-nitrophenyl)ethylamino]- n-phenylbenzamide (116)Prepared by reducing 85 (0.25 g, 0.7 mmol) using sodium


116 as light yellow crystals. Melting point 128°C–130°C; IR 3,367, 3,329, 3,053, 1,620, 1,514, 1,321 cm-1; 1H NMR



5.88 (s, 1H, NH-Ar), 6.85 (d, 1H, Ar-H, J=7.8 Hz), 7.1 (d, 2H, Ar-H, J=10.7 Hz), 7.21 (t, 1H, Ar-H, J=7.8 Hz), 7.26 (t, 1H, Ar-H, J=7.2 Hz), 7.35 (t, 2H, Ar-H, J=7.4 Hz), 7.41 (t, 3H, Ar-H, J=9.1 Hz), 7.81 (d, 2H, Ar-H, J=8.8 Hz), 10.22 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 45.52, 65.14, 106.30, 115.38, 116.03, 116.49, 117.25, 118.15, 123.69, 124.50, 124.82,

128.23, 134.99, 141.54, 142.95, 146.73, 160.44; MS (EI)

m/z: 378 (M+, 100%).

4-[2-(4-bromophenyl)-2-hydroxyethylamino]- n-phenylbenzamide (117)Prepared by reducing 86 (0.5 g, 1.2 mmol) using sodium


of 117 as white crystals. Melting point 202°C–204°C; IR 3,375, 3,061, 1,614, 1,323, 1,072 cm-1; 1H NMR



6.34 (s, 1H, NH-Ar), 6.69 (d, 2H, Ar-H, J=7.4 Hz), 7.04 (t, 1H, Ar-H, J=6.8 Hz), 7.31 (t, 2H, Ar-H, J=7 Hz), 7.38 (d, 2H, Ar-H, J=6.9 Hz), 7.55 (d, 2H, Ar-H, J=6.8 Hz), 7.76 (t, 4H, Ar-H, J=6.8 Hz), 9.78 (s, 1H, NH-CO); 13C-NMR (DMSO-d6): δ 51.01, 70.64, 111.51, 120.54, 120.65, 121.67, 123.41, 128.87, 128.94, 129.77, 131.40, 140.24, 143.86,

152.02, 165.75; MS (EI) m/z: 411 (M+, 100%).

4-[2-(4-chlorophenyl)-2-hydroxyethylamino]- n-phenylbenzamide (118)Prepared by reducing 88 (0.5 g, 1.4 mmol) using sodium


of 118 as white crystals. Melting point 198°C–200°C; IR 3,394, 3,358, 3,321, 3,057, 1,622, 1,321, 1,085 cm-1; 1H NMR (400 mHz, DMSO-d6): δ 3.24 (m, 1H, CH

2-N-Ar),

3.28 (m, 1H, CH2-N-Ar), 4.78 (s, 2H, Ar-H), 5.66 (s, 1H,

OH), 6.34 (s, 1H, NH-Ar), 6.7 (d, 2H, Ar-H, J=7.6 Hz), 7.04 (t, 1H, Ar-H, J=7.3 Hz), 7.31 (t, 2H, Ar-H, J=7.3 Hz), 7.43 (d, 4H, Ar-H, J=7.4 Hz), 7.78 (t, 4H, Ar-H, J=7 Hz), 9.81

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Drug Design, Development and Therapy 2014:8

Table 1 amounts of kit components used (in µl)

Sample Assay buffer

DPP-IV Inhibitor Substrate

Blank 50 0 0 50negative control 35 15 0 50Positive control 25 15 10 50Tested compounds 25 15 10 50

Abbreviation: DPP-iV, dipeptidyl peptidase-iV.


Dovepress

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al-Balas et al

(s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 49.70, 69.28, 110.17, 119.33, 120.31, 122.10, 127.14, 127.61, 128.43,

130.69, 138.86, 142.04, 150.68, 164.44; MS (EI) m/z: 367

(M+, 100%).

4-(2-hydroxy-2-p-tolylethylamino)- n-phenylbenzamide (119)Prepared by reducing 89 (0.5 g, 1.5 mmol) using sodium


119 as white crystals. Melting point 173°C–175°C; IR 3,387, 3,373, 3,059, 1,622, 1,319 cm-1; 1H NMR (400 mHz,

DMSO-d6): δ 2.28 (s, 3H, CH3), 3.18 (s, 1H, CH

2-N-Ar),

3.24 (s, 1H, CH2-N-Ar), 4.71 (s, 1H,CH-O), 5.47 (s, 1H,

OH), 6.30 (s, 1H, NH), 6.68 (d, 2H, Ar-H, J=5.2 Hz), 7.02 (s, 1H, Ar-H), 7.15 (s, 2H, Ar-H), 7.29 (s, 4H, Ar-H), 7.75

(s, 4H, Ar-H), 9.78 (s, 1H, CO-NH); 13C-NMR (DMSO-d6):

δ 21.23, 71.07, 111.46, 120.63, 121.52, 123.40, 126.48, 129.11, 129.78, 136.57, 140.26, 141.45, 152.1, 165.77; MS

(EI) m/z: 348 (M+, 100%).

4-(2-hydroxy-2-naphthalen-2-ylethylamino)- n-phenylbenzamide (120)Prepared by reducing 90 (0.5 g, 1.3 mmol) using sodium


of 120 as off-white crystals. Melting point 187°C–190°C; IR 3,373, 3,055, 1,620, 1,321 cm-1; 1H NMR (400 mHz,


2-

N-Ar), 4.85 (s, 1H, CH-O), 5.68 (d, 1H, NH, J=2.8 Hz), 6.74 (d, 2H, Ar-H, J=9.8 Hz), 7.06 (t, 1H, Ar-H, J=9.2 Hz), 7.32 (t, 2H, Ar-H, J=7.8 Hz), 7.51 (m, 2H, Ar-H), 7.61 (d, 2H, Ar-H, J=7.8 Hz), 7.77 (d, 2H, Ar-H, J=8.2 Hz), 7.8 (d, 2H, Ar-H, J=8.8 Hz), 7.92 (m, 4H, Ar-H), 9.78 (s, 1H, CO-NH); 13C-NMR (DMSO-d6): δ 50.64, 70.87, 110.98, 120.09, 121.10, 122.83, 124.48, 124.62, 125.58, 125.98, 127.46,

127.54, 127.73, 128.39, 129.24, 132.38, 132.79, 139.73,

141.47, 151.58, 165.20; MS (EI) m/z: 383 (M+, 100%).

DPP-iV enzymatic assayThe DPP-IV drug discovery kit marketed by Enzo Life Sci-

ences (Farmingdale, New York, NY, USA) was used for this

test. This kit includes human recombinant DPP-IV enzyme,

chromogenic substrate (H-Gly-Pro-pNA), a calibration stan-

dard (p-nitroaniline), an inhibitor (P32/98), and an assay buffer

(Tris, pH 7.5). The kit was stored at -70°C. On the day before testing, the kit components were defrosted in the refrigerator

and thawed at room temperature on the day of the test.

The inhibitor and compounds to be tested were all pre-

pared in DMSO solution and then diluted in assay buffer to

yield solutions at a concentration of 100 µM. Next, 5 µL of the substrate was diluted in 245 µL of assay buffer, and 5 µL of the enzyme was diluted in 245 µL of assay buffer.

The assay buffer was then distributed in all wells of the

plate in the amounts described in Table 1. The plate was then

placed in an oven at 37°C for 5 minutes to equilibrate. Next, 15 µL of the enzyme was added to each well except the blank. The inhibitor and the test compound were then added. The

plate was again incubated at 37°C for 10 minutes to allow interaction between the inhibitor and the enzyme. The final

step was adding the substrate to start the assay. After that, the

plate was read using a microplate reader every 2–3 minutes

for a total of 20 minutes.

Results and discussionDesign strategyThe design of the target compounds in this project involved a

combination of computer-aided and traditional drug design.

The design of the core structures started with a guide com-

pound (compound 1, see Figure 2) that had a satisfactory

inhibitory activity of 28% against the DDP-4 enzyme. Careful

modifications were then introduced based on a thorough

inspection of the three-dimensional structure of DPP-IV. The

proposed structures were docked inside the active site using

specialized in silico software (Discovery Studio 3.5) and the

possible binding energies were evaluated using computational

calculations that scored and ranked these energies.

The work started with docking of compound 1 inside the

active site using CDOCKER docking software (Figure 3),

that gave us an idea about the most likely orientation of this

compound in the active site of DPP-IV. Based on this pose, it

can be easily recognized that the aminobenzamide part of the

compound is important for binding since it forms a hydrogen

bond with the active site in addition to one π-π interaction. Based on the proper orientation the compound 1 had adopted

by matching the active site geometry and which also fostered

by performing a network of interactions with the receptor, the

aminobenzamide moiety was adopted as the core building

scaffold in this research, with addition of suitable extensions

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